Editing Plasmodium falciparum (section)

==Interaction with human immune system==
===Immune response===
A single anopheline mosquito can transmit hundreds of ''P. falciparum'' sporozoites in a single bite under experimental conditions, but, in nature, the number is generally less than 80.<ref>{{cite journal|last1=Beier|first1=JC|last2=Onyango|first2=FK|last3=Koros|first3=JK|last4=Ramadhan|first4=M|last5=Ogwang|first5=R|last6=Wirtz|first6=RA|last7=Koech|first7=DK|last8=Roberts|first8=CR|title=Quantitation of malaria sporozoites transmitted in vitro during salivation by wild Afrotropical Anopheles|journal=Medical and Veterinary Entomology|date=1991|volume=5|issue=1|pages=71–9|doi=10.1111/j.1365-2915.1991.tb00523.x|pmid=1768903|s2cid=27449694}}</ref> The sporozoites do not enter the bloodstream directly, but rather remain in the skin for two to three hours. About 15–20% of the sporozoites enter the lymphatic system, where they activate [[dendritic cells]], which send them for destruction by T lymphocytes ([[Cytotoxic T cell|CD8+ T cells]]). At 48 hours after infection, ''Plasmodium''-specific CD8+ T cells can be detected in the [[lymph nodes]] connected to the skin cells.<ref name=chakravarty>{{cite journal|last1=Chakravarty|first1=Sumana|last2=Cockburn|first2=Ian A|last3=Kuk|first3=Salih|last4=Overstreet|first4=Michael G|last5=Sacci|first5=John B|last6=Zavala|first6=Fidel|title=CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes|journal=Nature Medicine|date=2007|volume=13|issue=9|pages=1035–1041|doi=10.1038/nm1628|pmid=17704784|s2cid=17601147|doi-access=free}}</ref> Most of the sporozoites remaining in the skin tissue are subsequently killed by the [[innate immune system]]. The sporozoite glycoprotein specifically activates [[mast cells]]. The mast cells then produce [[Cytokine|signaling molecules]] such as [[TNFα]] and MIP-2, which activate cell eaters (professional phagocytes) such as [[neutrophils]] and [[macrophages]].<ref>{{cite journal|last1=Hopp|first1=Christine S.|last2=Sinnis|first2=Photini|title=The innate and adaptive response to mosquito saliva and Plasmodium sporozoites in the skin|journal=Annals of the New York Academy of Sciences|date=2015|volume=1342|issue=1|pages=37–43|doi=10.1111/nyas.12661|pmid=25694058|pmc=4405444|bibcode=2015NYASA1342...37H}}</ref>

Only a small number (0.5-5%) of sporozoites enter the bloodstream into the liver. In the liver, the activated CD8+ T cells from the lymph bind the sporozoites through the [[circumsporozoite protein]] (CSP).<ref name=chakravarty/> [[Antigen presentation]] by dendritic cells in the skin tissue to T cells is also a crucial process. From this stage onward, the parasites produce different proteins that help suppress communication of the immune cells.<ref>{{cite journal|last1=Gomes|first1=Pollyanna S.|last2=Bhardwaj|first2=Jyoti|last3=Rivera-Correa|first3=Juan|last4=Freire-De-Lima|first4=Celio G.|last5=Morrot|first5=Alexandre|title=Immune Escape Strategies of Malaria Parasites|journal=Frontiers in Microbiology|date=2016|volume=7|page=e1617|doi=10.3389/fmicb.2016.01617|pmid=27799922|pmc=5066453|doi-access=free}}</ref> Even at the height of the infection, when red blood cells (RBCs) are ruptured, the immune signals are not strong enough to activate macrophages or [[natural killer cells]].<ref>{{cite journal|last1=Artavanis-Tsakonas|first1=K|last2=Tongren|first2=JE|last3=Riley|first3=EM|title=The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology|journal=Clinical and Experimental Immunology|date=August 2003|volume=133|issue=2|pages=145–152|doi=10.1046/j.1365-2249.2003.02174.x|pmid=12869017|pmc=1808775}}{{open access}}</ref>

===Immune system evasion===
Although ''P. falciparum'' is easily recognized by the human immune system while in the bloodstream, it evades immunity by producing over 2,000 cell membrane antigens.<ref name=florens>{{cite journal|last1=Florens|first1=Laurence|last2=Washburn|first2=Michael P.|last3=Raine|first3=J. Dale|last4=Anthony|first4=Robert M.|last5=Grainger|first5=Munira|last6=Haynes|first6=J. David|last7=Moch|first7=J. Kathleen|last8=Muster|first8=Nemone|last9=Sacci|first9=John B.|last10=Tabb|first10=David L.|last11=Witney|first11=Adam A.|last12=Wolters|first12=Dirk|last13=Wu|first13=Yimin|last14=Gardner|first14=Malcolm J.|last15=Holder|first15=Anthony A.|last16=Sinden|first16=Robert E.|last17=Yates|first17=John R.|last18=Carucci|first18=Daniel J.|title=A proteomic view of the ''Plasmodium falciparum'' life cycle|journal=Nature|date=3 October 2002|volume=419|issue=6906|pages=520–526|doi=10.1038/nature01107|pmid=12368866|display-authors=8|bibcode=2002Natur.419..520F|s2cid=4412848|doi-access=free}}</ref> The initial infective stage sporozoites produce circumsporozoite protein (CSP), which binds to hepatocytes.<ref>{{cite journal|last1=Cerami|first1=Carla|last2=Frevert|first2=Ute|last3=Sinnis|first3=Photini|last4=Takacs|first4=Bela|last5=Clavijo|first5=Pedro|last6=Santos|first6=Manuel J.|last7=Nussenzweig|first7=Victor|title=The basolateral domain of the hepatocyte plasma membrane bears receptors for the circumsporozoite protein of ''Plasmodium falciparum'' sporozoites|journal=Cell|date=1992|volume=70|issue=6|pages=1021–1033|doi=10.1016/0092-8674(92)90251-7|pmid=1326407|s2cid=8825913}}</ref> Binding to and entering into the hepatocytes is aided by thrombospondin-related anonymous protein (TRAP).<ref>{{cite journal|last1=Baldacci|first1=Patricia|last2=Ménard|first2=Robert|title=The elusive malaria sporozoite in the mammalian host|journal=Molecular Microbiology|date=2004|volume=54|issue=2|pages=298–306|doi=10.1111/j.1365-2958.2004.04275.x|pmid=15469504|s2cid=30488807|doi-access=free}}</ref> TRAP and other secretory proteins (including sporozoite microneme protein essential for cell traversal 1, SPECT1 and SPECT2) from microneme allow the sporozoite to move through the blood, avoiding immune cells and penetrating hepatocytes.<ref name="vaughan">{{cite journal|last1=Vaughan|first1=Ashley M.|last2=Aly|first2=Ahmed S.I.|last3=Kappe|first3=Stefan H.I.|title=Malaria Parasite Pre-Erythrocytic Stage Infection: Gliding and Hiding|journal=Cell Host & Microbe|date=2008|volume=4|issue=3|pages=209–218|doi=10.1016/j.chom.2008.08.010|pmid=18779047|pmc=2610487}}</ref>

During erythrocyte invasion, merozoites release merozoite cap protein-1 (MCP1), apical membrane antigen 1 (AMA1), erythrocyte-binding antigens (EBA), myosin A tail domain interacting protein (MTIP), and [[merozoite surface protein]]s (MSPs).<ref name=florens/> Of these MSPs, MSP1 and MSP2 are primarily responsible for avoiding immune cells.<ref>{{cite journal|last1=Satchwell|first1=T. J.|title=Erythrocyte invasion receptors for ''Plasmodium falciparum'': new and old|journal=Transfusion Medicine|date=2016|volume=26|issue=2|pages=77–88|doi=10.1111/tme.12280|pmid=26862042|hdl=1983/2945cc98-49e8-4c37-a392-88e35fab588c|s2cid=7811400|url=https://research-information.bristol.ac.uk/en/publications/erythrocyte-invasion-receptors-for-plasmodium-falciparum(2945cc98-49e8-4c37-a392-88e35fab588c).html|hdl-access=free}}</ref> The virulence of ''P. falciparum'' is mediated by erythrocyte membrane proteins, which are produced by the schizonts and trophozoites inside the erythrocytes and are displayed on the erythrocyte membrane. [[PfEMP1]] is the most important, capable of acting as both an antigen and an adhesion molecule.<ref>{{cite journal|last1=Lalchhandama|first1=Kholhring|title=''Plasmodium falciparum'' erythrocyte membrane protein 1|journal=WikiJournal of Medicine|date=2017|volume=4|issue=1|pages=1–8|doi=10.15347/wjm/2017.004|doi-access=free}}</ref>